# The Mitochondria As Regulators Of Inflammation In Sepsis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Sepsis affects over 750,000 people per year in the United States and kills over a third of these patients. As
such, it has proved to be one of the greatest challenges to modern medicine. The cellular and molecular
events underlying the evolution of tissue injury and organ dysfunction during sepsis are under active
investigation and promise to guide the development of therapeutics. As of now the treatment of sepsis is
limited to treatment of the underlying infection and supportive care, without much of a individualized approach.
An area of intense recent focus is bioenergetics, the mitochondria, and metabolomics. Mitochondrial responses
are now known to orchestrate downstream cell signaling responses and outcomes, and thus greatly influence
organ function and outcomes. Others and we demonstrate that in the setting of sepsis, signals to the
mitochondria to regulate mitochondrial respiration and signaling from the mitochondria to regulate inflammatory
responses are not only important in the early response to sepsis, but also critical to the recovery of the cell.
 Our preliminary data show that sepsis patients have a profile of injured mitochondria. Additionally, that
aging is associated with decreased mitochondrial reserve and less dynamic responses. Mitochondrial health
and the ability to adapt to stimuli are crucial to the survival of organisms during stress. We show that during
this response mitochondrial respiration is altered and that the mitochondrion orchestrates this response by
initiating adaptive signaling responses. As a result mitochondria may become dysfunctional, and processes to
mitigate this, including removal of damaged mitochondria by autophagic cell signaling (controlled removal of
the organs) leads to decreased cell injury. Additionally reconstitution of a healthy mitochondrial population via
mitochondrial biogenesis is necessary to ensure survival.
 Based upon this we hypothesize the following: The baseline `health' of the mitochondrial network and
the ability to adapt through robust mitochondrial dynamic responses are critical to limit inflammation,
tissue injury, and organ dysfunction in sepsis.
 We will test this hypothesis by addressing the following specific aims:
Specific Aim 1. To determine how bioenergetics/mitochondrial health influences organ injury and
outcomes in sepsis.
Specific Aim 2. To examine how mitophagy/biogenesis inducing therapies can be harnessed for
therapeutic benefit in sepsis.
 Our laboratory has been investigating organ injury in sepsis and the role of mitochondrial signaling. These
novel studies will add insight into organ dysfunction in sepsis, have the promise of allowing determination of at
risk patients and a personalized approach to sepsis treatment, and will help guide the development of
therapeutics.

## Key facts

- **NIH application ID:** 9815463
- **Project number:** 5I01BX003924-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Brian Scott Zuckerbraun
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815463

## Citation

> US National Institutes of Health, RePORTER application 9815463, The Mitochondria As Regulators Of Inflammation In Sepsis (5I01BX003924-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815463. Licensed CC0.

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